Efficacy and Safety of Colesevelam Hydrochloride Modified-Release Tablets in Idiopathic Bile Acid Diarrhoea: A Randomized, Double-Blind, Placebo-Controlled Phase II Study
- Trial ID
- 2024-511993-55-00
- Protocol
- CB-01-33/01
- Sponsor
- Cosmo Technologies Limited
Trial statistics
Objectives
The primary objective of this study is to investigate the **efficacy** of two dose regimens of the investigational medicinal product, Colesevelam hydrochloride-MMX, compared to a matching placebo. This is assessed by the proportion of participants with idiopathic **bile acid diarrhoea** (BAD) who are stool consistency responders. This objective is clinically relevant as it aims to determine the potential of Colesevelam hydrochloride-MMX to improve stool consistency, which is a significant symptom impacting the quality of life in patients with idiopathic BAD.
The secondary objective is to evaluate the **efficacy**, **safety**, and **tolerability** of Colesevelam hydrochloride-MMX compared to placebo in participants diagnosed with idiopathic BAD. This evaluation is crucial for understanding the overall benefit-risk profile of the treatment, ensuring that it not only provides therapeutic benefits but also maintains an acceptable safety and tolerability profile for patients.
Participants
The clinical trial involves a total of **30 participants** diagnosed with **idiopathic bile acid diarrhoea (BAD)**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific criteria, including a diagnosis or symptoms consistent with type II idiopathic bile acid diarrhoea, and a fasting serum 7αC4 level greater than 46.0 ng/mL. Additionally, participants must have experienced at least one bowel movement with a stool consistency of Type 6 or 7 on the Bristol Stool Form Scale for at least four days per week during the screening period. The trial includes individuals who may be considered part of a vulnerable population. Lifestyle considerations such as the use of effective contraception methods are required for women of childbearing potential. The study ensures that all participants have provided informed consent and are capable of understanding the study's nature and purpose, including potential risks and side effects. Compliance with baseline diary entry is also a prerequisite for participation.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, placebo-controlled, phase II study designed to evaluate the efficacy and safety of a novel modified-release tablet formulation of **colesevelam hydrochloride** in patients with **idiopathic bile acid diarrhoea (BAD)**. The trial involves two different dose regimens of the active product compared to a placebo. The primary objective is to assess the proportion of participants who are stool consistency responders, defined as those experiencing a ≥50% reduction in the number of days with at least one stool of Type 6 or 7 on the Bristol Stool Form Scale (BSFS) compared to baseline. The trial is expected to conclude by June 2026, with recruitment starting in June 2025.
Participants will be involved in the study for a maximum of 56 days, corresponding to the treatment period. The study visits include an initial **screening visit** to confirm eligibility based on criteria such as age, diagnosis, and compliance with baseline diary entries. Following randomization, participants will attend follow-up visits at Weeks 2, 4, and 8 to monitor treatment response and safety. The **end-of-study visit** will occur at Week 8, where the primary and secondary endpoints will be evaluated. Secondary endpoints include stool frequency response, remission of diarrhoea, and urgency remission.
Inclusion criteria require participants to be adults aged 18 years or older with a diagnosis or symptoms of idiopathic BAD, as well as the ability to comprehend the study's nature and comply with its requirements. Women of childbearing potential must adhere to specific contraceptive measures. Conditions for early termination from the study include non-compliance with study procedures or the occurrence of adverse events that necessitate withdrawal. The investigational product, **Colesevelam hydrochloride-MMX® 900 mg modified-release tablets**, is administered orally, with a maximum daily dose of 3600 mg. The placebo tablets are identical in appearance to maintain blinding. The study is not classified as a low-intervention trial, and it is conducted under the sponsorship of Cosmo Technologies Ltd.
Treatment
The clinical trial involves the administration of **Colesevelam hydrochloride-MMX®** 900 mg modified-release tablets, which are designed to evaluate their efficacy and safety in patients with idiopathic bile acid diarrhoea (BAD). The experimental medication, **Colesevelam hydrochloride**, is presented in a **modified-release tablet** form, allowing for controlled release of the active substance. The tablets are administered **orally**. The dosing regimen includes a maximum daily dose of **3600 mg**, with a total maximum dose of **86400 mg** over a treatment period of up to **56 days**. The active substance, **Colesevelam hydrochloride**, is of chemical origin and is classified as a polymer. The pharmaceutical product is manufactured by Cosmo Technologies Ltd.
In addition to the experimental medication, the study employs a **placebo** control, which consists of **Colesevelam hydrochloride-MMX® modified-release placebo tablets**. These placebo tablets are designed to match the appearance and administration route of the active medication but do not contain the active substance. The use of a placebo is integral to maintaining the double-blind nature of the trial, ensuring unbiased assessment of the investigational product's efficacy. The placebo tablets are administered in the same manner as the active treatment, following the same dosing schedule to ensure consistency across study participants.
Efficacy
The efficacy of the investigational medicinal product, **colesevelam hydrochloride**, will be assessed in a randomized, double-blind, placebo-controlled phase II clinical trial involving patients with idiopathic bile acid diarrhoea (BAD). The primary endpoint for evaluating efficacy is the proportion of study participants who are stool consistency responders at Week 8. A stool consistency responder is defined as a participant who experiences a ≥50% reduction in the number of days with at least one stool that has a consistency of Type 6 or 7 on the 7-point Bristol Stool Form Scale (BSFS) compared with baseline.
Secondary endpoints include the proportion of stool consistency responders at Weeks 2 and 4, the proportion of participants achieving remission of diarrhoea as per Hjortswang criteria at Week 8, and the proportion of stool frequency responders at Week 8. Additionally, the trial will assess the proportion of participants achieving remission in urgency, defined as a score of <3 on the urgency numerical rating scale at Weeks 2, 4, and 8. The comparison of adverse drug reactions between treatments after 8 weeks will also be evaluated. Efficacy assessments will be conducted at specified timepoints using validated scales and criteria to ensure accurate and reliable data collection and analysis.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Informed consent: signed written informed consent before inclusion in the study;
- Sex and age: men/women, ≥18 years old inclusive;
- Diagnosis or symptoms of bile acid diarrhoea: suspected or diagnosed bile acid diarrhoea or subjects presenting with symptoms compatible with bile acid diarrhoea, including subjects with suspected functional diarrhoea or IBS-D as per Rome IV criteria, and subjects with a ≥6-month-old cholecystectomy, who fulfil the following criteria (both a. and b. conditions must be fulfilled): a1. have a fasting serum 7αC4 >46.0 ng/mL; or a2. positive SeHCAT test (SeHCAT<10%) (performed within the last 18 months before screening) independently of the 7αC4 fasting serum value; or a3. positive SeHCAT test (SeHCAT<10%) (performed more than 18 months but within the last 6 years before screening) and fasting serum value 7αC4 ≥ 31 ng/mL; or a4. fasting serum 7αC4 ≥ 31 ng/mL and ≤ 46 ng/mL, with a daily number of watery stools (Type 6 or 7 in the 7-point BSFS) more than 1 per day over 7 days; AND b. have at least 4 days per week during the screening period with ≥1 bowel movement with a stool consistency of Type 6 or 7 in the 7-point BSFS.
- Contraception (women only): women of childbearing potential must use at least one of the following highly effective methods of contraception: a. Hormonal combined oral, intravaginal, or transdermal, contraceptives for at least 2 months before the screening visit b. Progestogen-only hormonal oral, implantable, or injectable contraceptives for at least 2 months before the screening visit c. A non-hormonal intrauterine device [IUD] or an intrauterine hormone-releasing system (IUS) for at least 2 months before the screening visit d. Bilateral tubal occlusion e. A sterile sexual partner f. True abstinence, i.e., refraining from heterosexual intercourse when this is in line with the preferred and usual lifestyle of the subject. Women of non-childbearing potential or in postmenopausal status must have been in that status for at least one year. For all women of childbearing potential, serum pregnancy test result must be negative at screening;
- Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the study;
- Compliance with baseline diary entry: a minimum of 4 consecutive or non-consecutive days of completed diary entries within a 7-day period are necessary (except for participants fulfilling criterion 3 a4 who must have at least 7 consecutive diary entries within a 7-day period).
Exclusion Criteria
- Prior and concomitant gastrointestinal diseases: a) Current or recurrent disease that could affect the ileum and the enterohepatic circulation of bile acids, including ileal resection or bypass, short bowel syndrome, radiation enteritis, chronic pancreatitis, known small intestine bacterial overgrowth; b) Cholecystectomy within 6 months prior to the screening visit; c) Inflammatory bowel disease, including known microscopic colitis; d) Bowel obstruction; e) Biliary obstruction; f) Acute suspected or proven infectious (viral or bacterial) gastroenteritis within the 8 weeks prior to screening; g) Acute suspected or proven gastroenteritis within the 8 weeks prior to screening; h) Positive for Clostridium difficile toxins as detected by appropriate specific test; i) Coeliac disease, if any of the followings apply: Positive coeliac serology (e.g., anti-tissue transglutaminase [anti-TTG] IgA or equivalent) without a confirmed prior diagnosis of coeliac disease, unless false positive determined by the investigator; Diagnosis of coeliac disease within 6 months prior to the screening visit; Known or suspected non-adherence to a gluten-free diet, based on clinical assessment or patient history; Persistent gastrointestinal symptoms or abnormal laboratory findings (e.g., elevated anti-TTG, iron deficiency, or abnormal inflammatory markers) suggestive of ongoing disease activity. Participants with prior diagnosis (i.e. made > 6 months prior to screening), who are on a strict gluten-free diet for ≥ 6 months with no recent (within 6 months) dietary lapses or gluten reintroduction, have no on-going coeliac disease-related symptoms, and have no abnormal serologic or histologic laboratory findings suggestive of active disease, may be included. A positive serology can also be considered provided they are false positive confirmed by the investigator. j) Current or recurrent diseases that could affect the colon including diverticulitis, collagenous colitis, colonic resection, toxic megacolon, fistula, perforation or abscess;
- Prior and concomitant diseases other than gastroenteric: a) Fasting triglycerides level above 3.4 mmol/L (300.9 mg/dL); b) Current or relevant previous history of serious, severe or unstable (acute or progressive) physical or psychiatric illness; c) Any medical disorder that may require treatment or make the patient unlikely to fully complete the study or any condition that presents undue risk from the study medication or procedures; d) History of malignancy within the last 5 years prior to screening, with the following exception: localized malignancies that were completely resected, do not require on-going treatment, and have been in complete remission for at least 3 years prior to screening. e) Hyperthyroidism;
- Previous unsuccessful treatments: unsuccessfully treating BAD with bile acid sequestrants (cholestyramine, colestipol or colesevelam) unless the reason for treatment failure was due to non-compliance/lack of tolerability;
- Prior and concomitant treatments (not to be discontinued solely due to participation in the trial): a) Treatment with other bile acid sequestrants must be stopped within 3 days before screening; b) Treatment with glucagon like peptide (GLP)-1 or GLP-2 receptor agonists (e.g., liraglutide) within 4 weeks before screening; c) Treatment with cyclosporine within 1 month before screening; d) Any concomitant medication, which colesevelam may have an interaction with, whose administration cannot be suspended for the duration of the study and which cannot be administered separated from the study drug (at least 4 h prior to or after the administration of colesevelam); e) Any concomitant medication for diarrhoea-predominant irritable bowel syndrome within 1 week prior to screening; f) Treatment with antidiarrheal drugs except loperamide (which is not permitted in the 48 hours prior to screening; g) Treatment with drugs with a known pharmacological activity on 5-hydroxytryptamine (5-HT)4, 5-HT2b or 5-HT3 receptors (e.g., tegaserod, ondansetron, tropisetron, granisetron, dolasetron, mirtazapine cilansetron, alosetron) within 2 weeks before screening; h) Treatment with drugs affecting the function of the gastrointestinal tract, including opioids (e.g. morphine, oxycodone, codeine, methadone, fentanyl, tramadol) unless taken at a stable dose for at least 4 weeks prior to screening and maintained unchanged throughout the study, anticholinergic drugs (e.g., dicyclomine, hyoscyamine, propantheline), anti-nausea drugs (e.g. trimethobenzamide, promethazine, prochlorperazine, dimenhydrinate, hydroxyzine), laxative drugs (e.g. lactulose, sorbitol or polyethylene glycol preparations), prokinetic drugs (e.g. cisapride, metoclopramide, prucalopride, domperidone) within 4 weeks before screening; i) Rectal treatments (other than topical steroids for the treatment of haemorrhoids) within 2 weeks before screening; J) Treatment with immunosuppressant or immunomodulator agents including monoclonal antibodies (for instance, infliximab, adalimumab, azathioprine, 6-mercaptopurine, cyclosporine, vedolizumab, tofacitinib, filgotinib, ozanimod, etc.), within 4 weeks prior to screening; k) Treatment with ustekinumab within 16 weeks prior to screening (due to its longer half-life compared other Disease Modifying AntiRheumatic Drugs - DMARD); l) Treatment with antibiotics within 2 weeks before screening; m) Treatment with non-steroidal anti-inflammatory drugs (e.g. aspirin or ibuprofen) within 7 days prior to screening. Prophylactic use of a stable dose of aspirin up to 100 mg/day for cardiac disease is permitted;
- Inflammatory markers: C-reactive protein >1.0 mg/dL, abnormal faecal calprotectin >100 µg/g; (if considered clinically significant by the Investigator as indicating an active inflammatory, infectious, or systemic condition that may interfere with patient safety or BAD assessment);
- Allergy: ascertained or presumptive hypersensitivity to the active principle and/or formulations’ ingredients; history of anaphylaxis to drugs or allergic reactions in general, which the Investigator considers may affect the outcome of the study;
- Pregnancy (women only): pregnant or lactating women or women wishing to become pregnant in the 3 months following the screening visit; positive or missing pregnancy test at screening;
- Liver function: chronic liver disease (including primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, chronic viral hepatitis, or cirrhosis of any aetiology) or clinically significant liver enzyme abnormality as evidenced by elevated aspartate aminotransferase, alanine aminotransferase >2.5 times upper limit of normal or total bilirubin >1.5 times upper limit of normal, with the following exceptions: Participants with metabolic-associated fatty liver disease (MAFLD previously NAFLD) without evidence of advanced fibrosis may be enrolled if liver function is stable and no other exclusion applies; Isolated indirect hyperbilirubinemia (e.g., consistent with Gilbert’s syndrome) is not exclusionary if other liver function parameters are within specified protocol limits and the participant is clinically stable.
- Investigative drug trials: participation in experimental therapeutic trials in the last 3 months before screening;
- Physical findings: clinically relevant abnormal physical findings which could interfere with the objectives of the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 30 Jun 2025 | 14 |
 Denmark | Recruiting | 30 Jun 2025 | 18 |
 Italy | Recruiting | 30 Jun 2025 | 50 |
 Romania | Recruiting | 30 Jun 2025 | 12 |
 Spain | Recruiting | 30 Jun 2025 | 26 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Colesevelam hydrochloride-MMX® modified-release placebo tablets | Placebo | N/A | — | — | — | N/A |
Colesevelam hydrochloride-MMX® 900 mg modified-release
tablets | Test | MODIFIED-RELEASE TABLET | ORAL | 3600 | 56 | PRD11502744 |